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WO2012061698A2 - Composés utiles en tant que modulateurs de trpm8 - Google Patents

Composés utiles en tant que modulateurs de trpm8 Download PDF

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Publication number
WO2012061698A2
WO2012061698A2 PCT/US2011/059312 US2011059312W WO2012061698A2 WO 2012061698 A2 WO2012061698 A2 WO 2012061698A2 US 2011059312 W US2011059312 W US 2011059312W WO 2012061698 A2 WO2012061698 A2 WO 2012061698A2
Authority
WO
WIPO (PCT)
Prior art keywords
optionally substituted
ylmethyl
thiophen
compound
nmr
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2011/059312
Other languages
English (en)
Other versions
WO2012061698A3 (fr
WO2012061698A9 (fr
Inventor
Chad Priest
Alain Noncovich
Andrew Patron
Jane Ung
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Firmenich Inc
Original Assignee
Senomyx Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to MX2016009042A priority Critical patent/MX359640B/es
Priority to AU2011323245A priority patent/AU2011323245B2/en
Priority to EP18199830.3A priority patent/EP3470407B1/fr
Priority to CN2011800534925A priority patent/CN103201279A/zh
Priority to RU2013125846A priority patent/RU2608109C2/ru
Priority to EP11838869.3A priority patent/EP2635572B1/fr
Priority to CA2816983A priority patent/CA2816983A1/fr
Priority to US13/883,349 priority patent/US9394287B2/en
Priority to JP2013537863A priority patent/JP5990526B2/ja
Priority to MX2013005001A priority patent/MX340488B/es
Priority to PH1/2013/500907A priority patent/PH12013500907A1/en
Priority to BR112013011188-7A priority patent/BR112013011188B1/pt
Application filed by Senomyx Inc filed Critical Senomyx Inc
Publication of WO2012061698A2 publication Critical patent/WO2012061698A2/fr
Publication of WO2012061698A3 publication Critical patent/WO2012061698A3/fr
Publication of WO2012061698A9 publication Critical patent/WO2012061698A9/fr
Anticipated expiration legal-status Critical
Priority to ZA2013/03421A priority patent/ZA201303421B/en
Priority to US15/205,608 priority patent/US10016418B2/en
Priority to US15/994,235 priority patent/US10953007B2/en
Ceased legal-status Critical Current

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Definitions

  • the present invention relates to compounds useful as modulators of TRPM8.
  • TRPM8 is a channel involved in the chemesthetic sensation, such as cool to cold temperatures as well as the sensation of known cooling agents, such as Menthol and Icilin.
  • TRPM8 modulators have deficiencies with regard to strength and/or duraton of effect, skin and/or mucosa irritation, odor, taste, solubility, and/or toxicity.
  • the present invention provides a compound having structural
  • Ar is optionally substituted aryl, optionally substituted carbocyclyl, or optionally substituted heteroaryl;
  • R 2a , R 2b , R 3 , R 4 , R 5 , and R 6 are independently hydrogen or lower alkyl; hAr is an optionally substituted five- or six-membered heteroaryl containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur; and
  • R 1 is optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl.
  • the present invention provides a personal product comprising a compound of the present invention, or a salt or solvate thereof.
  • the present invention provides a method of modulating transient receptor potential channel melastatin member 8 (TRPM8) comprising contacting the receptor with a compound of the present invention, or a salt or solvate thereof.
  • TRPM8 transient receptor potential channel melastatin member 8
  • the present invention provides a method of modulating the cooling sensation of a composition comprising combining the composition with a compound of the present invention, or a salt or solvate thereof, to form a modified composition.
  • the present invention provides a method of inducing a cooling sensation in a human or animal comprising contacting the human or animal with a compound of the present invention, or a salt or solvate thereof.
  • present compound(s) or “compound(s) of the present invention” refers to compounds encompassed by structural formulae disclosed herein and includes any subgenus and specific compounds within these formulae whose structure is disclosed herein.
  • Compounds may be identified either by their chemical structure and/or chemical name.
  • the chemical structure is determinative of the identity of the compound.
  • the compounds described herein may contain one or more chiral centers and/or double bonds and therefore, may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers or diastereomers.
  • the chemical structures depicted herein encompass all possible enantiomers and stereoisomers of the illustrated compounds including the stereoisomerically pure form (e.g. , geometrically pure, enantiomerically pure or diastereomerically pure) and enantiomeric and stereoisomeric mixtures.
  • Enantiomeric and stereoisomeric mixtures can be resolved into their component enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known to the skilled artisan.
  • the compounds may also exist in several tautomeric forms including the enol form, the keto form and mixtures thereof.
  • the chemical structures depicted herein encompass all possible tautomeric forms of the illustrated compounds.
  • the compounds described also include isotopically labeled compounds where one or more atoms have an atomic mass different from the atomic mass conventionally found in nature. Examples of isotopes that may be incorporated into the
  • compounds of the invention include, but are not limited to, H, H, C, C, N, O, O, etc.
  • Compounds may exist in unsolvated forms as well as solvated forms, including hydrated forms and as N-oxides. In general, compounds may be hydrated, solvated or N-oxides.
  • Alkyl by itself or as part of another substituent, refers to a saturated branched, straight-chain or cyclic monovalent hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane.
  • alkyl includes "cycloakyl” as defined herein below.
  • Typical alkyl groups include, but are not limited to, methyl; ethyl; propyls such as propan-l-yl, propan-2-yl (isopropyl), cyclopropan-l-yl, etc.; butanyls such as butan-l-yl, butan-2-yl (sec-butyl), 2-methyl-propan-l-yl (isobutyl),
  • an alkyl group comprises from 1 to 20 carbon atoms (C 1 -C 20 alkyl). In other embodiments, an alkyl group comprises from 1 to 10 carbon atoms (Ci-Cio alkyl). In still other embodiments, an alkyl group comprises from 1 to 6 carbon atoms (Ci-C 6 alkyl). Ci-C 6 alkyl is also known as "lower alkyl”.
  • alkylene refers to a divalent alkyl.
  • -CH 2 CH 3 is an ethyl
  • -CH 2 CH 2 - is an ethylene
  • alkylene by itself or as part of another substituent, refers to a saturated or unsaturated, branched, straight-chain or cyclic divalent hydrocarbon radical derived by the removal of two hydrogen atoms from a single carbon atom or two different carbon atoms of a parent alkane, alkene or alkyne.
  • alkylene includes "cycloalkylene” as defined herein below.
  • alkylene is specifically intended to include groups having any degree or level of saturation, i.e., groups having exclusively single carbon-carbon bonds, groups having one or more double carbon-carbon bonds, groups having one or more triple carbon-carbon bonds and groups having mixtures of single, double and triple carbon-carbon bonds.
  • an alkylene group comprises from 1 to 20 carbon atoms (C 1 -C 20 alkylene).
  • an alkylene group comprises from 1 to 10 carbon atoms (C 1 -C 10 alkylene). In still other embodiments, an alkylene group comprises from 1 to 6 carbon atoms (Ci-C 6 alkylene).
  • alkenyl by itself or as part of another substituent, refers to an unsaturated branched, straight-chain or cyclic monovalent hydrocarbon radical having at least one carbon-carbon double bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkene.
  • alkenyl includes “cycloalkenyl” as defined herein below. The group may be in either the cis or trans conformation about the double bond(s).
  • Typical alkenyl groups include, but are not limited to, ethenyl; propenyls such as prop-l-en-l-yl, prop-l-en-2-yl, prop-2-en-l-yl (allyl), prop-2-en-2-yl, cycloprop-l-en-l-yl; cycloprop-2-en-l-yl; butenyls such as but-l-en-l-yl, but-l-en-2-yl, 2-methyl-prop-l-en-l-yl, but-2-en-l-yl , but-2-en-l-yl, but-2-en-2-yl, buta-l,3-dien-l-yl, buta-l,3-dien-2-yl, cyclobut-l-en-l-yl, cyclobut-l-en-3-yl, cyclobuta-l,3-dien-l-yl, etc.; and the like.
  • Alkynyl by itself or as part of another substituent refers to an unsaturated branched, straight-chain or cyclic monovalent hydrocarbon radical having at least one carbon-carbon triple bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkyne.
  • Typical alkynyl groups include, but are not limited to, ethynyl; propynyls such as prop-l-yn-l-yl, prop-2-yn-l-yl, etc.; butynyls such as but-l-yn-l-yl, but-l-yn-3-yl, but-3-yn-l-yl, etc.; and the like.
  • Alkoxy by itself or as part of another substituent, refers to a radical of the formula -O-R 199 , where R 199 is alkyl or substituted alkyl as defined herein.
  • Acyl by itself or as part of another substituent refers to a radical -C(0)R 200 , where R 200 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroarylalkyl or substituted heteroarylalkyl as defined herein.
  • Representative examples include, but are not limited to formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl and the like.
  • Aryl by itself or as part of another substituent, refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system, as defined herein.
  • Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phen
  • an aryl group comprises from 6 to 20 carbon atoms (C 6 -C 2 o aryl). In other embodiments, an aryl group comprises from 6 to 15 carbon atoms (C 6 -C 15 aryl). In still other embodiments, an aryl group comprises from 6 to 15 carbon atoms (C 6 -Cio aryl).
  • Arylalkyl by itself or as part of another substituent, refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp 3 carbon atom, is replaced with an aryl group as, as defined herein. That is, arylakyl can also be considered as an alkyl substituted by aryl.
  • Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-l-yl, 2-phenylethen-l-yl, naphthylmethyl,
  • an arylalkyl group is (C 6 -C30) arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (C 1 -C 10 ) alkyl and the aryl moiety is (C 6 -C 2 o) aryl.
  • an arylalkyl group is (C 6 -C 2 o) arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (Ci-Cs) alkyl and the aryl moiety is (C 6 -C 12 ) aryl.
  • an arylalkyl group is (C 6 -C 15 ) arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (C 1 -C5) alkyl and the aryl moiety is (C 6 -C 10 ) aryl.
  • Carbocyclic or “Carbocyclyl,” by itself or as part of another substituent, refers to a saturated or partially saturated, buy noy aromatic, cyclic monovalent hydrocarbon radical, including cycloalkyl, cycloalkenyl, and cycloalkynyl as defined herein.
  • Typical carbocyclyl groups include, but are not limited to, groups derived from cyclopropane, cyclobutane, cyclopentane, cyclohexane, and the like.
  • the cycloalkyl group comprises from 3 to 10 ring atoms (C 3 -C 10 cycloalkyl).
  • the cycloalkyl group comprises from 3 to 7 ring atoms (C3-C7 cycloalkyl).
  • the carbocyclyl may be further substituted by one or more heteroatoms including, but not limited to, N, P, O, S, and Si, which attach to the carbon atoms of the cycloalkyl via monovalent or multivalent bond.
  • Heteroalkyl by themselves or as part of other substituents, refer to alkyl groups, in which one or more of the carbon atoms, are each, independently of one another, replaced with the same or different heteroatoms or heteroatomic groups.
  • Typical heteroatoms or heteroatomic groups which can replace the carbon atoms include, but are not limited to, -0-, -S-, -N-, -Si-, -NH-, -S(O)-, -S(0) 2 -, -S(0)NH-, -S(0) 2 NH- and the like and combinations thereof.
  • the heteroatoms or heteroatomic groups may be placed at any interior position of the alkyl group.
  • R 201 , R 202 , R 203 , R 204 , R 205 , R 206 , R 207 and R 208 are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted
  • heteroalkyl heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl.
  • Heterocyclic or “Heterocyclyl,”by itself or as part of another substituent, refers to a carbocyclic radical in which one or more carbon atoms are independently replaced with the same or different heteroatom.
  • the heterocyclyl may be further substituted by one or more heteroatoms including, but not limited to, N, P, O, S, and Si, which attach to the carbon atoms of the heterocyclyl via monovalent or multivalent bond.
  • Typical heteroatoms to replace the carbon atom(s) include, but are not limited to, N, P, O, S, Si, etc.
  • Typical heterocyclyl groups include, but are not limited to, groups derived from epoxides, azirines, thiiranes, imidazolidine, morpholine, piperazine, piperidine, pyrazolidine, pyrrolidone, quinuclidine, and the like.
  • the heterocyclyl group comprises from 3 to 10 ring atoms (3-10 membered heterocyclyl) In other embodiments, the heterocyclyl group comprise from 5 to 7 ring atoms (5-7 membered heterocyclyl).
  • a cycloheteroalkyl group may be substituted at a heteroatom, for example, a nitrogen atom, with a (Ci-C 6 ) alkyl group.
  • N-methyl-imidazolidinyl, N-methyl-morpholinyl, N-methyl-piperazinyl, N-methyl-piperidinyl, N-methyl-pyrazolidinyl and N-methyl-pyrrolidinyl are included within the definition of "heterocyclyl.”
  • a heterocyclyl group may be attached to the remainder of the molecule via a ring carbon atom or a ring heteroatom.
  • Halo by itself or as part of another substituent refers to a radical -F, -CI, -Br or -I.
  • Heteroaryl by itself or as part of another substituent, refers to a monovalent heteroaromatic radical derived by the removal of one hydrogen atom from a single atom of a parent heteroaromatic ring systems, as defined herein.
  • Typical heteroaryl groups include, but are not limited to, groups derived from acridine, ⁇ -carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole,
  • the heteroaryl group comprises from 5 to 20 ring atoms (5-20 membered heteroaryl). In other embodiments, the heteroaryl group comprises from 5 to 10 ring atoms (5-10 membered heteroaryl).
  • Exemplary heteroaryl groups include those derived from furan, thiophene, pyrrole, benzothiophene, benzofuran, benzimidazole, indole, pyridine, pyrazole, quinoline, imidazole, oxazole, isoxazole and pyrazine.
  • Heteroarylalkyl by itself or as part of another substituent refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp 3 carbon atom, is replaced with a heteroaryl group. Where specific alkyl moieties are intended, the nomenclature heteroarylalkanyl, heteroarylakenyl and/or heteroarylalkynyl is used.
  • the heteroarylalkyl group is a 6-21 membered heteroarylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the heteroarylalkyl is (Ci-C 6 ) alkyl and the heteroaryl moiety is a 5-15-membered heteroaryl.
  • the heteroarylalkyl is a 6-13 membered heteroarylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety is (C 1 -C3) alkyl and the heteroaryl moiety is a 5-10 membered heteroaryl.
  • Protecting group refers to a grouping of atoms that when attached to a reactive functional group in a molecule masks, reduces or prevents reactivity of the functional group.
  • protecting groups can be found in Green et ah, "Protective Groups in Organic Chemistry", (Wiley, 2 nd ed. 1991) and Harrison et al., “Compendium of Synthetic Organic Methods", Vols. 1-8 (John Wiley and Sons, 1971-1996).
  • Representative amino protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl,
  • CBZ benzyloxycarbonyl
  • Boc tert-butoxycarbonyl
  • TMS trimethylsilyl
  • hydroxy protecting groups include, but are not limited to, those where the hydroxy group is either acylated or alkylated such as benzyl, and trityl ethers as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers and allyl ethers.
  • Salt refers to a salt of a compound, which possesses the desired pharmacological activity of the parent compound.
  • Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid,
  • 2-naphthalenesulfonic acid 4-toluenesulfonic acid, camphorsulfonic acid,
  • Solvate means a compound formed by solvation (the combination of solvent molecules with molecules or ions of the solute), or an aggregate that consists of a solute ion or molecule, i.e., a compound of the present invention, with one or more solvent molecules.
  • solvation the combination of solvent molecules with molecules or ions of the solute
  • aggregate that consists of a solute ion or molecule, i.e., a compound of the present invention, with one or more solvent molecules.
  • water the solvent
  • the corresponding solvate is "hydrate”.
  • N-oxide also known as amine oxide or amine-N-oxide, means a compound that derives from a compound of the present invention via oxidation of an amine group of the compound of the present invention.
  • Substituted when used to modify a specified group or radical, means that one or more hydrogen atoms of the specified group or radical are each, independently of one another, replaced with the same or different substituent(s).
  • R a is selected from the group consisting of alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl; each R b is independently hydrogen or R a ; and each R c is independently R b or alternatively, the two R c s may be taken together with the nitrogen atom to which they are bonded form a 4-, 5-, 6- or 7-membered cycloheteroalkyl which may optionally include from 1 to 4 of the same or different additional heteroatoms selected from the group consisting of O, N and S.
  • -NR C R C is meant to include -NH 2 , -NH-alkyl, N-pyrrolidinyl and
  • a substituted alkyl is meant to include - alkylene-O-alkyl, -alkylene-heteroaryl, -alkylene-cycloheteroalkyl, -alkylene-C(0)OR b , - alkylene-C(0)NR b R b , and -CH 2 -CH 2 -C(0)-CH 3 .
  • the one or more substituent groups, taken together with the atoms to which they are bonded, may form a cyclic ring including cycloalkyl and cycloheteroalkyl.
  • substituent groups useful for substituting unsaturated carbon atoms in the specified group or radical include, but are not limited to, -R a , halo, -O " , -OR b , -SR b , -S " , -NR C R C , trihalomethyl, -CF 3 , -CN, -OCN, -SCN, -NO, -N0 2 , -N 3 , -S(0) 2 R b , -S(0) 2 0 " , -S(0) 2 OR b , -OS(0) 2 R b , -OS(0) 2 0 " , -OS(0) 2 OR b , -P(0)(0 ) 2 , -P(0)(OR b )(0 ),
  • Substituent groups useful for substituting nitrogen atoms in heteroalkyl and cycloheteroalkyl groups include, but are not limited to, -R a , -O " , -OR b , -SR b , -S " , -NR C R C , trihalomethyl, -CF 3 , -CN, -NO, -N0 2 , -S(0) 2 R b , -S(0) 2 0 " , -S(0) 2 OR b , -OS(0) 2 R b ,
  • substituted specifically envisions and allows for one or more substitutions that are common in the art. However, it is generally understood by those skilled in the art that the substituents should be selected so as to not adversely affect the useful characteristics of the compound or adversely interfere with its function.
  • Suitable substituents may include, for example, halogen groups, perfluoroalkyl groups, perfluoroalkoxy groups, alkyl groups, alkenyl groups, alkynyl groups, hydroxy groups, oxo groups, mercapto groups, alkylthio groups, alkoxy groups, aryl or heteroaryl groups, aryloxy or heteroaryloxy groups, arylalkyl or heteroarylalkyl groups, arylalkoxy or heteroarylalkoxy groups, amino groups, alkyl- and dialkylamino groups, carbamoyl groups, alkylcarbonyl groups, carboxyl groups,
  • alkoxycarbonyl groups alkylaminocarbonyl groups, dialkylamino carbonyl groups, arylcarbonyl groups, aryloxycarbonyl groups, alkylsulfonyl groups, arylsulfonyl groups, cycloalkyl groups, cyano groups, Ci-C 6 alkylthio groups, arylthio groups, nitro groups, keto groups, acyl groups, boronate or boronyl groups, phosphate or phosphonyl groups, sulfamyl groups, sulfonyl groups, sulfinyl groups, and combinations thereof.
  • substituted combinations such as "substituted arylalkyl,” either the aryl or the alkyl group may be substituted, or both the aryl and the alkyl groups may be substituted with one or more substituents. Additionally, in some cases, suitable substituents may combine to form one or more rings as known to those of skill in the art.
  • optionally substituted denotes the presence or absence of the substituent group.
  • optionally substituted alkyl includes both unsubstituted alkyl and substituted alkyl.
  • the substituents used to substitute a specified group can be further substituted, typically with one or more of the same or different groups selected from the various groups specified above.
  • Carrier refers to a diluent, adjuvant, excipient or vehicle with which a compound is administered.
  • a "personal product”, as used herein, refers to any product that is used by or useful for a person or animal, optionally in contact with the person or animal during its intended use, e.g., in surface contact such as skin or mucosa contact with the person or animal during its intended use.
  • an "ingestible composition” includes any substance that, either alone or together with another substance, can be taken by mouth whether intended for consumption or not.
  • the ingestible composition includes both "food or beverage products” and “non- edible products”.
  • Food or beverage products it is meant any edible product intended for consumption by humans or animals, including solids, semi-solids, or liquids (e.g., beverages).
  • non-edible products or “noncomestible composition” includes any product or composition that can be taken by humans or animals for purposes other than consumption or as food or beverage.
  • the non-edible product or noncomestible composition includes supplements, nutraceuticals, functional food products (e.g., any fresh or processed food claimed to have a health-promoting and/or disease-preventing properties beyond the basic nutritional function of supplying nutrients), pharmaceutical and over the counter medications, oral care products such as dentifrices and mouthwashes, cosmetic products such as sweetened lip balms and other personal care products that may or may not contain any sweetener.
  • a "ingestibly acceptable carrier or excipient” is a medium and/or composition that is used to prepare a desired dispersed dosage form of the inventive compound, in order to administer the inventive compound in a dispersed/diluted form, so that the biological effectiveness of the inventive compound is maximized.
  • the medium and/or composition may be in any form depending on the intended use of a product, e.g., solid, semi-solid, liquid, paste, gel, lotion, cream, foamy material, suspension, solution, or any combinations thereof (such as a liquid containing solid contents).
  • Ingestibly acceptable carriers includes many common food ingredients, such as water at neutral, acidic, or basic pH, fruit or vegetable juices, vinegar, marinades, beer, wine, natural water/fat emulsions such as milk or condensed milk, edible oils and shortenings, fatty acids and their alkyl esters, low molecular weight oligomers of propylene glycol, glyceryl esters of fatty acids, and dispersions or emulsions of such hydrophobic substances in aqueous media, salts such as sodium chloride, wheat flours, solvents such as ethanol, solid edible diluents such as vegetable powders or flours, or other liquid vehicles; dispersion or suspension aids; surface active agents; isotonic agents;
  • thickening or emulsifying agents thickening or emulsifying agents, preservatives; solid binders; lubricants and the like.
  • a “flavor” herein refers to the perception of taste in a subject, which include sweet, sour, salty, bitter and umami (also known as savory).
  • the subject may be a human or an animal.
  • a “flavoring agent” herein refers to a compound or the ingestibly acceptable salt or solvate thereof that induces a flavor or taste in an animal or a human.
  • the flavoring agent can be natural, semi-synthetic, or synthetic.
  • a “modulator” herein refers to a compound that can regulate the activity of TRPM8. Such regulation includes activating TRPM8, blocking TRPM8, or potentiating/reducing the activation of TRPM8. That is, the modulators include agonists, antagonists, enhancers, and etc.
  • chemesthesis or “chemesthetic sensation” herein refers to the sensibility of bodily surface, e.g., the skin and/or mucosal surfaces which arise either when the bodily surface is exposed to heat or coldness or when chemical compounds activate receptors associated with senses that mediate pain, touch, and thermal/cold perception. Particularly, these chemical-induced reactions do not fit into the traditional sense categories of taste and smell.
  • chemesthetic sensations include the burn-like irritation from chili pepper, the coolness of menthol in mouthwashes and topical analgesic creams, the stinging or tingling of carbonation in the nose and mouth, and the tear-induction of onions.
  • chemesthetic sensations can arise by direct chemical activation of ion channels on sensory nerve fibers, e.g. TRPM8. Because chemoresponsive nerve fibers are present in all types of skin, chemesthetic sensations can be aroused from anywhere on the body's surface as well as from mucosal surfaces in the nose, mouth, eyes, etc.
  • a “chemesthetic sensation modifier” or “chemesthetic sensation modifying agent” herein refers to a compound, or a salt or solvate thereof, that modulates, including enhancing or potentiating, inducing, or blocking, the chemesthetic sensation in an animal or a human.
  • a “chemesthetic sensation modulating amount” herein refers to an amount of a compound of the present invention that is sufficient to alter (either induce, increase, or decrease) the chemesthetic sensation in a personal product, sufficiently to be perceived by an animal or human subject. In many embodiments of the invention, at least about 0.001 ppm of the present compound would need to be present in order for most animal or human subjects to perceive a modulation of the chemesthetic sensation in a personal product comprising the present compound.
  • a broad range of concentration that would typically be employed in order to economically provide a desirable degree of chemesthetic sensation modulation can be from about 0.001 ppm to 1000 ppm, or from about 0.01 ppm to about 500 ppm, or from about 0.05 ppm to about 300 ppm, or from about 0.1 ppm to about 200 ppm, or from about 0.5 ppm to about 150 ppm, or from about 1 ppm to about 100 ppm.
  • a "chemesthetic sensation inducing amount” or “chemesthetic sensation increasing amount” herein refers to an amount of a compound that is sufficient to induce or increase a chemesthetic sensation as perceived by an animal or a human.
  • a broad range of a chemesthetic sensation inducing/increasing amount can be from about 0.001 ppm to 100 ppm, or a narrow range from about 0.1 ppm to about 10 ppm.
  • Alternative ranges of chemesthetic sensation inducing/increasing amounts can be from about 0.01 ppm to about 30 ppm, from about 0.05 ppm to about 15 ppm, from about 0.1 ppm to about 5 ppm, or from about 0.1 ppm to about 3 ppm.
  • the present invention provides a compound having structural Formula (I):
  • Ar is optionally substituted aryl, optionally substituted carbocyclyl, or optionally substituted heteroaryl;
  • R 2a , R 2b , R 3 , R 4 , R 5 , and R 6 are independently hydrogen or lower alkyl
  • hAr is an optionally substituted five-membered heteroaryl containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur;
  • R 1 is optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl.
  • Ar is optionally substituted aryl, and the optionally substituted aryl is optionally substituted phenyl.
  • Ar is optionally substituted heteroaryl, wherein the heteroaryl is a five- or six-membered heteroaryl containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the optionally substituted heteroaryl is an optionally substituted group selected from the group consisting of pyrrolyl, furanyl, thienyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyridyl, pyrimidyl, and triazinyl.
  • the optional substituent as mentioned above is one or more of group selected from the group consisting of alkyl, heteroalkyl, alkenyl, alkoxy, hydroxyl, amino, N-alkyl amino, N-dialkyl amino, halo, nitro, cyano, acyl, carboxyl, carboxyl ester, or amide; or two substituents, together with the atoms to which they are attached, form an optionally substituted carbocyclyl or heterocyclyl containing one or more heteroatom(s) selected from nitrogen, oxygen, and sulfur.
  • R 2b , R 3 , R 4 , R 5 , and R 6 are all hydrogen.
  • hAr is selected from the group consisting of pyrrolyl, furanyl, thienyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, isoxazolyl, and
  • R 1 is optionally substituted alkyl, wherein the alkyl is straight, branched, cyclic, or a combination thereof.
  • R 1 is optionally substituted aryl or optionally substituted heteroaryl.
  • aryl and heteroaryl include, but are not limited to, phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidyl, and triazinyl, each of which is optionally substituted.
  • X J -X 2 is 0-CH 2 , 0-CH(CH 3 ), or 0-CH(CH 2 CH 3 ).
  • X -X 2 is cyclopropyl, cyclobutyl, or cyclopentyl.
  • the compound in one embodiment, can be represented by a structural Formula (II):
  • Ar is optionally substituted aryl, optionally substituted carbocyclyl, or optionally substituted heteroaryl;
  • Y is oxygen or sulfur
  • Z is nitrogen or CR
  • R is hydrogen or lower alkyl
  • R 2a , R 2b , R 3 , R 4 , R 5 , and R 6 are independently hydrogen or lower alkyl;
  • R 1 is optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl;
  • n 0, 1, 2, or 3;
  • each R 2 is independently optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, alkoxy, hydroxyl, amino, N-alkyl amino, N- dialkyl amino, halo, nitro, cyano, acyl, carboxyl, carboxyl ester, or amide.
  • the compound in one embodiment, can be represented by a structural Formula (III):
  • Ar is optionally substituted aryl, optionally substituted carbocyclyl, or optionally substituted heteroaryl;
  • R 2a , R 2b , R 3 , R 4 , R 5 , and R 6 are independently hydrogen or lower alkyl
  • Z 1 and Z 2 are independently nitrogen or CH, provided that Z 1 and Z 2 are not both nitrogen;
  • R 1 is optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl.
  • Ar is optionally substituted phenyl.
  • R 1 is optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • R 2a and R 2b are hydrogen. In one embodiment of Formula (III), R 2a is hydrogen, and R 2b is lower alkyl.
  • the compound in one embodiment, can be represented by a structural Formula (IV):
  • X is a bicyclic heteroaryl
  • hAr is an optionally substituted five-membered heteroaryl containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur;
  • R 1 is optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl.
  • hAr is thienyl or furanyl.
  • X is optionally substituted benzo furanyl.
  • R 1 is optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • the present compounds are selected from the group consisting of the compound of Table A and Table B below:
  • the compounds of the present invention can be used modulators, e.g., agonists, of the TRPM8 receptor in personal products for modulating, e. inducing, chemesthetic sensations, particularly the cold or cool sensations.
  • modulators e.g., agonists, of the TRPM8 receptor in personal products for modulating, e. inducing, chemesthetic sensations, particularly the cold or cool sensations.
  • the present compounds are important to the flavorings and fragrance industry because they can increase or induce/generate a cooling or cold sensation which is often associated with freshness and cleanliness.
  • the present compounds also have repellent effect on insects, therapeutic effect in antitumor treatments (e.g. an influencing of prostate tumors), activity in the treatment of inflammatory pain/hyperalgesia, and efficacy (as TRPM8 antagonists) in the treatment of bladder syndrome or overactive bladder.
  • the personal product can be provided as a composition, which comprises one or more of the present compound and optionally at least one carrier.
  • the composition can be in any physical form, such as a solid, semi-solid, plaster, solution, suspension, lotion, cream, foam, gel, paste, emulsion, or a combination thereof.
  • Examples of the composition include, but are not limited to, a pharmaceutical composition, an ingestible composition, a chemesthetic concentrate, a personal care composition, and a combination thereof.
  • the composition comprises a chemesthetic sensation modulating amount of the present compound.
  • the composition comprises a chemesthetic sensation inducing amount of the present compound.
  • the chemesthetic sensation is a cold or cooling sensation.
  • the present compound is in a concentration ranging from about 0.0001 ppm to 100,000 ppm. In another embodiment of the composition, the present compound is in a concentration ranging from about 0.001 ppm to 10,000 ppm. In another embodiment of the composition, the present compound is in a concentration ranging from about 0.01 ppm to 1,000 ppm. In another embodiment of the composition, the present compound is in a concentration ranging from about 0.1 ppm to 500 ppm. In another embodiment of the composition, the present compound is in a concentration ranging from about 1 ppm to 500 ppm. In another embodiment of the composition, the present compound is in a concentration ranging from about 10 ppm to 500 ppm. In another embodiment of the composition, the present compound is in a concentration ranging from about 1 ppm to 400 ppm.
  • the present ingestible composition typically comprises one or more compounds of the present invention and at least one ingestibly acceptable carrier.
  • the ingestible composition includes both "food or beverage products” and “non-edible products".
  • food or beverage products it is meant any edible product intended for consumption by humans or animals, including solids, semi-solids, or liquids (e.g., beverages).
  • non-edible products or “noncomestible composition” includes nutraceutical compositions, dietary supplements, nutritional compositions, and functional food products (e.g., any fresh or processed food claimed to have a health-promoting and/or disease-preventing properties beyond the basic nutritional function of supplying nutrients).
  • the present compounds are added to food or beverage products or formulations.
  • Examples of food and beverage products or formulations include, but are not limited to coatings, frostings, or glazes for comestible products or any entity included in the Soup category, the Dried Processed Food category, the Beverage category, the Ready Meal category, the Canned or Preserved Food category, the Frozen Processed Food category, the Chilled Processed Food category, the Snack Food category, the Baked Goods category, the Confectionary category, the Dairy Product category, the Ice Cream category, the Meal Replacement category, the Pasta and Noodle category, and the Sauces, Dressings,
  • Condiments category the Baby Food category, and/or the Spreads category.
  • Soup category refers to canned/preserved, dehydrated, instant, chilled
  • soup(s) means a food prepared from meat, poultry, fish, vegetables, grains, fruit and other ingredients, cooked in a liquid which may include visible pieces of some or all of these ingredients. It may be clear (as a broth) or thick (as a chowder), smooth, pureed or chunky, ready-to-serve, semi-condensed or condensed and may be served hot or cold, as a first course or as the main course of a meal or as a between meal snack (sipped like a beverage). Soup may be used as an ingredient for preparing other meal components and may range from broths (consomme) to sauces (cream or cheese-based soups).
  • “Dehydrated and Culinary Food Category” usually means: (i) Cooking aid products such as: powders, granules, pastes, concentrated liquid products, including concentrated bouillon, bouillon and bouillon like products in pressed cubes, tablets or powder or granulated form, which are sold separately as a finished product or as an ingredient within a product, sauces and recipe mixes (regardless of technology); (ii) Meal solutions products such as: dehydrated and freeze dried soups, including dehydrated soup mixes, dehydrated instant soups, dehydrated ready-to-cook soups, dehydrated or ambient preparations of ready-made dishes, meals and single serve entrees including pasta, potato and rice dishes; and (iii) Meal embellishment products such as: condiments, marinades, salad dressings, salad toppings, dips, breading, batter mixes, shelf stable spreads, barbecue sauces, liquid recipe mixes, concentrates, sauces or sauce mixes, including recipe mixes for salad, sold as a finished product or as an ingredient within a product, whether dehydrated,
  • the Beverage category usually means beverages, beverage mixes and concentrates, including but not limited to, carbonated and non-carbonated beverages, alcoholic and non-alcoholic beverages, ready to drink beverages, liquid concentrate formulations for preparing beverages such as sodas, and dry powdered beverage precursor mixes.
  • the Beverage category also includes the alcoholic drinks, the soft drinks, sports drinks, isotonic beverages, and hot drinks.
  • the alcoholic drinks include, but are not limited to beer, cider/perry, FABs, wine, and spirits.
  • the soft drinks include, but are not limited to carbonates, such as colas and non-cola carbonates; fruit juice, such as juice, nectars, juice drinks and fruit flavored drinks; bottled water, which includes sparkling water, spring water and purified/table water; functional drinks, which can be carbonated or still and include sport, energy or elixir drinks; concentrates, such as liquid and powder concentrates in ready to drink measure.
  • the drinks either hot or cold, include, but are not limited to coffee or ice coffee, such as fresh, instant, and combined coffee; tea or ice tea, such as black, green, white, oolong, and flavored tea; and other drinks including flavor-, malt- or plant-based powders, granules, blocks or tablets mixed with milk or water.
  • the Snack Food category generally refers to any food that can be a light informal meal including, but not limited to Sweet and savory snacks and snack bars.
  • snack food include, but are not limited to fruit snacks, chips/crisps, extruded snacks, tortilla/corn chips, popcorn, pretzels, nuts and other sweet and savory snacks.
  • snack bars include, but are not limited to granola/muesli bars, breakfast bars, energy bars, fruit bars and other snack bars.
  • the Baked Goods category generally refers to any edible product the process of preparing which involves exposure to heat or excessive sunlight.
  • baked goods include, but are not limited to bread, buns, cookies, muffins, cereal, toaster pastries, pastries, waffles, tortillas, biscuits, pies, bagels, tarts, quiches, cake, any baked foods, and any combination thereof.
  • the Ice Cream category generally refers to frozen dessert containing cream and sugar and flavoring.
  • ice cream include, but are not limited to: impulse ice cream; take-home ice cream; frozen yoghurt and artisanal ice cream; soy, oat, bean (e.g., red bean and mung bean), and rice-based ice creams.
  • the Confectionary category generally refers to edible product that is sweet to the taste.
  • Examples of confectionary include, but are not limited to candies, gelatins, chocolate confectionery, sugar confectionery, gum, and the likes and any combination products.
  • the Meal Replacement category generally refers to any food intended to replace the normal meals, particularly for people having health or fitness concerns. Examples of meal replacement include, but are not limited to slimming products and convalescence products.
  • the Ready Meal category generally refers to any food that can be served as meal without extensive preparation or processing.
  • the ready meal includes products that have had recipe "skills" added to them by the manufacturer, resulting in a high degree of readiness, completion and convenience.
  • Examples of ready meal include, but are not limited to canned/preserved, frozen, dried, chilled ready meals; dinner mixes; frozen pizza; chilled pizza; and prepared salads.
  • the Pasta and Noodle category includes any pastas and/or noodles including, but not limited to canned, dried and chilled/fresh pasta; and plain, instant, chilled, frozen and snack noodles.
  • the Canned/Preserved Food category includes, but is not limited to canned/preserved meat and meat products, fish/seafood, vegetables, tomatoes, beans, fruit, ready meals, soup, pasta, and other canned/preserved foods.
  • the Frozen Processed Food category includes, but is not limited to frozen processed red meat, processed poultry, processed fish/seafood, processed vegetables, meat substitutes, processed potatoes, bakery products, desserts, ready meals, pizza, soup, noodles, and other frozen food.
  • the Dried Processed Food category includes, but is not limited to rice, dessert mixes, dried ready meals, dehydrated soup, instant soup, dried pasta, plain noodles, and instant noodles.
  • the Chill Processed Food category includes, but is not limited to chilled processed meats, processed fish/seafood products, lunch kits, fresh cut fruits, ready meals, pizza, prepared salads, soup, fresh pasta and noodles.
  • the Sauces, Dressings and Condiments category includes, but is not limited to tomato pastes and purees, bouillon/stock cubes, herbs and spices, monosodium glutamate (MSG), table sauces, soy based sauces, pasta sauces, wet/cooking sauces, dry sauces/powder mixes, ketchup, mayonnaise, mustard, salad dressings, vinaigrettes, dips, pickled products, and other sauces, dressings and condiments.
  • MSG monosodium glutamate
  • soy based sauces pasta sauces
  • wet/cooking sauces dry sauces/powder mixes
  • ketchup mayonnaise, mustard, salad dressings, vinaigrettes, dips, pickled products, and other sauces, dressings and condiments.
  • the Baby Food category includes, but is note limited to milk- or soybean-based formula; and prepared, dried and other baby food.
  • the Spreads category includes, but is not limited to jams and preserves, honey, chocolate spreads, nut based spreads, and yeast based spreads.
  • the Dairy Product category generally refers to edible product produced from mammal's milk.
  • dairy product include, but are not limited to drinking milk products, cheese, yoghurt and sour milk drinks, and other dairy products.
  • comestible compositions include one or more confectioneries, chocolate confectionery, tablets, countlines, bagged selflines/softlines, boxed assortments, standard boxed assortments, twist wrapped miniatures, seasonal chocolate, chocolate with toys, alfajores, other chocolate confectionery, mints, standard mints, power mints, boiled sweets, pastilles, gums, jellies and chews, toffees, caramels and nougat, medicated confectionery, lollipops, liquorices, other sugar
  • confectionery gum, chewing gum, sugarized gum, sugar-free gum, functional gum, bubble gum, bread, packaged/industrial bread, unpackaged/artisanal bread, pastries, cakes, packaged/industrial cakes, unpackaged/artisanal cakes, cookies, chocolate coated biscuits, sandwich biscuits, filled biscuits, savory biscuits and crackers, bread substitutes, breakfast cereals, rte cereals, family breakfast cereals, flakes, muesli, other cereals, children's breakfast cereals, hot cereals, ice cream, impulse ice cream, single portion dairy ice cream, single portion water ice cream, multi-pack dairy ice cream, multi-pack water ice cream, take-home ice cream, take-home dairy ice cream, ice cream desserts, bulk ice cream, take-home water ice cream, frozen yoghurt, artisanal ice cream, dairy products, milk, fresh/pasteurized milk, full fat fresh/pasteurized milk, semi skimmed fresh/pasteurized milk, long-life/uht milk, full fat long life
  • condiments tomato pastes and purees, bouillon/stock cubes, stock cubes, gravy granules, liquid stocks and fonds, herbs and spices, fermented sauces, soy based sauces, pasta sauces, wet sauces, dry sauces/powder mixes, ketchup, mayonnaise, regular mayonnaise, mustard, salad dressings, regular salad dressings, low fat salad dressings, vinaigrettes, dips, pickled products, other sauces, dressings and condiments, baby food, milk formula, standard milk formula, follow-on milk formula, toddler milk formula, hypoallergenic milk formula, prepared baby food, dried baby food, other baby food, spreads, jams and preserves, honey, chocolate spreads, nut-based spreads, and yeast-based spreads.
  • Exemplary comestible compositions also include confectioneries, bakery products, ice creams, dairy products, sweet and savory snacks, snack bars, meal replacement products, ready meals, soups, pastas, noodles, canned foods, frozen foods, dried foods, chilled foods, oils and fats, baby foods, or spreads or a mixture thereof.
  • the pharmaceutical composition comprises one or more compounds of the present invention and at least one pharmaceutically acceptable carrier.
  • the pharmaceutical composition includes both the prescription medications and the over-the- counter medications.
  • the present compound may or may not be the therapeutically active ingredient in the pharmaceutical composition.
  • the pharmaceutical composition can be used by any mode of administration known to one skilled in the art, particularly by topical administration, such as application of analgesic cream to the skin surface.
  • over the counter (OTC) product and oral hygiene product generally refer to product for household and/or personal use which may be sold without a prescription and/or without a visit to a medical professional.
  • Examples of the OTC products include, but are not limited to vitamins and dietary supplements; topical analgesics and/or anesthetic; cough, cold and allergy remedies; antihistamines and/or allergy remedies; and combinations thereof.
  • Vitamins and dietary supplements include, but are not limited to vitamins, dietary supplements, tonics/bottled nutritive drinks, child-specific vitamins, dietary supplements, any other products of or relating to or providing nutrition, and combinations thereof.
  • Topical analgesics and/or anesthetic include any topical creams/ointments/gels used to alleviate superficial or deep-seated aches and pains, e.g. muscle pain; teething gel; patches with analgesic ingredient; and combinations thereof.
  • Cough, cold and allergy remedies include, but are not limited to decongestants, cough remedies, pharyngeal preparations, medicated confectionery, antihistamines and child-specific cough, cold and allergy remedies; and combination products.
  • Antihistamines and/or allergy remedies include, but are not limited to any systemic treatments for hay fever, nasal allergies, insect bites and stings.
  • oral hygiene product include, but are not limited to mouth cleaning strips, toothpaste, toothbrushes, mouthwashes/dental rinses, denture care, mouth fresheners, mouth
  • moisturizers at-home teeth whiteners and dental floss.
  • a "personal care composition” refers to a composition to be directly applied to the skin, mucosal, or other surface area of the body.
  • personal care composition include, but are not limited to, an oral care composition, such as toothpaste, chewing gum, breath refresher, dentifrices, and mouthwashes; a skincare or haircare composition, such as sunscreen cream, sunburn lotions, shaving cream, plasters, shampoos, conditioners, face cleaners, soaps, bath oils or bath foam, antiperspirants, and deodorant; a cosmetic composition, such as moisturizer, lip balms, foundation, etc.; an insect repellent composition; or an insecticide composition.
  • an oral care composition such as toothpaste, chewing gum, breath refresher, dentifrices, and mouthwashes
  • a skincare or haircare composition such as sunscreen cream, sunburn lotions, shaving cream, plasters, shampoos, conditioners, face cleaners, soaps, bath oils or bath foam, antiperspirants, and deodorant
  • a cosmetic composition such as moisturizer,
  • the present compounds are provided in a chemesthetic concentrate formulation, e.g., suitable for subsequent processing to produce a ready-to-use (i.e., ready-to-serve) product.
  • a chemesthetic concentrate formulation it is meant a formulation which should be reconstituted with one or more diluting medium to become a ready-to-use composition.
  • ready-to-use composition is used herein interchangeably with "ingestible composition”, which denotes any substance that, either alone or together with another substance, can be taken by mouth whether intended for consumption or not.
  • the ready-to-use composition includes a composition that can be directly consumed by a human or animal.
  • the chemesthetic concentrate formulation is typically used by mixing with or diluted by one or more diluting medium, e.g., any consumable or ingestible ingredient or product, to impart or modify a chemesthetic sensation to the diluting medium.
  • diluting medium e.g., any consumable or ingestible ingredient or product
  • Such a use process is often referred to as reconstitution.
  • the reconstitution can be conducted in a household setting or an industrial setting.
  • a frozen fruit juice concentrate can be reconstituted with water or other aqueous medium by a consumer in a kitchen to obtain the ready-to-use fruit juice beverage.
  • a mouthwash concentrate can be reconstituted with water or other aqueous medium by a manufacture in large industrial scales to produce the ready-to-use mouthwash.
  • the chemesthetic concentrate formulation has the present compound and optionally a flavoring agent and/or flavor modifying agent in a concentration higher than the ready-to-use composition, the chemesthetic concentrate formulation is typically not suitable for being consumed directly without reconstitution.
  • a chemesthetic concentrate formulation There are many benefits of using and producing a chemesthetic concentrate formulation. For example, one benefit is the reduction in weight and volume for transportation as the chemesthetic concentrate formulation can be reconstituted at the time of usage by the addition of suitable solvent, solid or liquid.
  • the chemesthetic concentrate formulation comprises i) as chemesthetic sensation modifying ingredient, a compound of the present invention; ii) a carrier; and iii) optionally at least one adjuvant.
  • chemesthetic sensation modifying ingredient denotes that the compound of the present invention acts as a modulator of a chemesthetic sensation (such as, a cold or cooling sensation modulator) in the formulation.
  • carrier denotes a usually inactive accessory substance, such as solvents, binders, or other inert medium, which is used in combination with the present compound and one or more optional adjuvants to form the formulation.
  • water or starch can be a carrier for a flavoring concentrate formulation.
  • the carrier is the same as the diluting medium for reconstituting the chemesthetic concentrate formulation; and in other embodiments, the carrier is different from the diluting medium.
  • carrier as used herein includes, but is not limited to, ingestibly acceptable carrier.
  • the term “adjuvant” denotes an additive which supplements, stabilizes, maintains, or enhances the intended function or effectiveness of the active ingredient, such as the compound of the present invention.
  • the at least one adjuvant comprises one or more flavoring agents.
  • the flavoring agent may be of any flavor known to one skilled in the art or consumers, such as the flavor of chocolate, coffee, tea, mocha, French vanilla, peanut butter, chai, or combinations thereof.
  • the at least one adjuvant comprises one or more sweeteners.
  • the at least one adjuvant comprises one or more ingredients selected from the group consisting of a emulsifier, a stabilizer, an antimicrobial preservative, an antioxidant, vitamins, minerals, fats, starches, protein concentrates and isolates, salts, and combinations thereof.
  • a emulsifier emulsifier, stabilizers, antimicrobial preservatives, antioxidants, vitamins, minerals, fats, starches, protein concentrates and isolates, salts, and combinations thereof.
  • emulsifiers, stabilizers, antimicrobial preservatives, antioxidants, vitamins, minerals, fats, starches, protein concentrates and isolates, and salts are described in U.S. 6,468,576, the contents of which are hereby incorporated by reference in its entirety for all purposes.
  • the present chemesthetic concentrate formulation can be in a form selected from the group consisting of liquid including solution and suspension, solid, foamy material, paste, gel, cream, and a combination thereof, such as a liquid containing certain amount of solid contents.
  • the chemesthetic concentrate formulation is in form of a liquid including aqueous-based and nonaqueous-based.
  • the present chemesthetic concentrate formulation can be carbonated or non-carbonated.
  • the chemesthetic concentrate formulation may further comprise a freezing point depressant, nucleating agent, or both as the at least one adjuvant.
  • the freezing point depressant is a ingestibly acceptable compound or agent which can depress the freezing point of a liquid or solvent to which the compound or agent is added. That is, a liquid or solution containing the freezing point depressant has a lower freezing point than the liquid or solvent without the freezing point depressant.
  • the freezing point depressant may also lower the water activity of the flavoring concentrate formulation.
  • the examples of the freezing point depressant include, but are not limited to, carbohydrates, oils, ethyl alcohol, polyol, e.g., glycerol, and combinations thereof.
  • the nucleating agent denotes a ingestibly acceptable compound or agent which is able to facilitate nucleation.
  • the presence of nucleating agent in the flavoring concentrate formulation can improve the mouthfeel of the frozen slushes of a frozen slush and to help maintain the physical properties and performance of the slush at freezing temperatures by increasing the number of desirable ice crystallization centers.
  • nucleating agents include, but are not limited to, calcium silicate, calcium carbonate, titanium dioxide, and combinations thereof.
  • the chemesthetic concentrate formulation is formulated to have a low water activity for extended shelf life.
  • Water activity is the ratio of the vapor pressure of water in a formulation to the vapor pressure of pure water at the same temperature.
  • the chemesthetic concentrate formulation has a water activity of less than about 0.85.
  • the chemesthetic concentrate formulation has a water activity of less than about 0.80.
  • the chemesthetic concentrate formulation has a water activity of less than about 0.75.
  • the chemesthetic concentrate formulation has the present compound in a concentration that is at least 2 times of the concentration of the compound in a ready-to-use composition.
  • the chemesthetic concentrate formulation has the present compound in a concentration that is at least 5 times of the concentration of the compound in a ready-to-use composition. In one embodiment, the chemesthetic concentrate formulation has the present compound in a concentration that is at least 10 times of the concentration of the compound in a ready-to-use composition. In one embodiment, the chemesthetic concentrate formulation has the present compound in a concentration that is at least 15 times of the concentration of the compound in a ready-to-use composition. In one embodiment, the chemesthetic concentrate formulation has the present compound in a concentration that is at least 20 times of the concentration of the compound in a ready-to-use composition.
  • the chemesthetic concentrate formulation has the present compound in a concentration that is at least 30 times of the concentration of the compound in a ready-to-use composition. In one embodiment, the chemesthetic concentrate formulation has the present compound in a concentration that is at least 40 times of the concentration of the compound in a ready-to-use composition. In one embodiment, the chemesthetic concentrate formulation has the present compound in a concentration that is at least 50 times of the concentration of the compound in a ready-to-use composition. In one embodiment, the chemesthetic concentrate formulation has the present compound in a concentration that is at least 60 times of the concentration of the compound in a ready-to-use composition. In one embodiment, the chemesthetic concentrate formulation has the present compound in a concentration that is up to 100 times of the concentration of the compound in a ready-to-use composition.
  • the personal product can be provided as a textile product.
  • the textile product includes, but are not limited to, shirts, pants, socks, towels, and etc.
  • the present compound can be applied to the textile product in any suitable methods known to one skilled in the art.
  • the present compound can be associated with the textile by spin- coating, imprinting, in the form of microencapsulation, direct incorporation into the textile material (e.g. extruding), covalent coupling of suitable derivatives of the modulators (via suitable spacer/linker groups, with the help of which the molecule is reversibly or irreversibly bonded to the packaging material).
  • the personal product can be provided as packaging materials.
  • packaging materials include paper and plastic wrapping, which may be in various processing forms including fibers, fabrics, and moldings.
  • the present compound can be applied to the packaging material in any suitable methods known to one skilled in the art.
  • the present compound can be associated with the packaging material by spin-coating, imprinting, in the form of microencapsulation, direct incorporation into the packaging material (e.g. extruding), covalent coupling of suitable derivatives of the modulators (via suitable spacer/linker groups, with the help of which the molecule is reversibly or irreversibly bonded to the packaging material.
  • the compounds of the present invention can be used for modulating transient receptor potential channel melastatin member 8 (TRPM8) by contacting the receptor with a compound of the present invention.
  • TRPM8 transient receptor potential channel melastatin member 8
  • This modulation process can be carried out either in vitro or in vivo.
  • the compound is a TRPM8 receptor agonist.
  • the compounds of the present invention can also be formulated into a precursor of the above-described compositions.
  • precursor it is meant a substance or composition from which another composition, such as those described above, is formed.
  • the present compounds may be provided as a concentrated formulation or composition which may be further mixed or diluted to form another composition suitable for consumption or personal use.
  • the present compounds can be used to modify the chemesthetic sensation of a composition by contacting the present compounds with the composition to form a taste- modified composition.
  • the present compounds can convey or impart a cooling taste to a composition.
  • the present invention provides a method of modulating the cold or cooling sensation of a composition comprising combining the composition with a compound of the present invention, or a salt or solvate thereof, to form a modified
  • the present invention provides a method of inducing a cold or cooling sensation in a human or animal by contacting the human or animal with a compound of the present invention.
  • a mammalian cell line derivative which stably expresses hTRPM8 was used in biological assays in association with testing the present compounds with cool-tasting or - feeling properties (Servant et al. US 2007/0259354 Al and references cited therein). Typical compound concentrations tested were 100 ⁇ , 50 ⁇ , 10 ⁇ , 1 ⁇ , and 0.5 ⁇ . The present compounds have shown strong activity as agonists of hTRPM8. Assay results for compounds are illustrated in Table 1 below. Specifically, the Examples listed in Table 1, i.e., Compounds Al to Compounds U10 are the specific compounds, i.e., Examples, as described above.
  • Reactions using compounds having functional groups may be performed on compounds with functional groups that may be protected.
  • a "protected” compound or derivatives means derivatives of a compound where one or more reactive site or sites or functional groups are blocked with protecting groups.
  • Protected derivatives are useful in the preparation of the compounds of the present invention or in themselves; the protected derivatives may be the biologically active agent.
  • An example of a comprehensive text listing suitable protecting groups may be found in T. W. Greene, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, Inc. 1999.
  • Step 1 A Step l .B
  • L1AIH 4 (1.0 M in diethyl ether, 24.07 mmol, 24.07 mL, 1.0 eq) was added to the solution slowly, changing the solution color from yellow to orange. The mixture was allowed to stir overnight as the temperature increases to room temperature. The reaction was quenched with 1.0 N aqueous sodium hydroxide solution at 0°C. Majority of the volatiles were evaporated and the remaining aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine and then dried over sodium sulfate.
  • N-(oxazol-2-yl)-N-(thiophen-2-ylmethyl)-2-(p-tolyloxy)acetamide (example 4) (430 mgs, 1.313 mmol) was dissolved in N, N-dimethylformamide.
  • Sodium hydride (60% in mineral oil, 55 mgs, 1.38 mmol) was added at 0°C and a bubbler was attached to observe gas evolution. The reaction was stirred with gradual warming to room temperature until gas evolution ceased.
  • 2-bromoacetonitrile (92 ⁇ ⁇ , 1.38 mmol) was added at room temperature and the reaction was allowed to stir overnight.
  • Example 59 N 2-(4-ethylphenoxy)-N-(pyridin-3-yl)-N-(thiophen-2-ylmethyl)acetamide;
  • Example 59 Prepared in a similar manner to example 21 from 2-(4-ethylphenoxy)acetyl chloride and N- (thiophen-2-ylmethyl)pyridin-3-amine.
  • Example 142 2-(3-fluorophenoxy)-N-(pyridin-3-yl)-N-(thiophen-2-ylmethyl)acetamide;
  • Example 142 Prepared in a similar manner to example 21 from 2-(3-fluorophenoxy)acetyl chloride and N- (thiophen-2-ylmethyl)pyridin-3-amine.
  • Example 157 Prepared in a similar manner to example 21 from 2-(p-tolyloxy)acetyl chloride and N- cyclohexylpyridin-2-amine.
  • Example 159 Prepared in a similar manner to example 21 from 2-(p-tolyloxy)acetyl chloride and N-
  • Examplel72 Prepared in a similar manner to example 6 from (E)-3-p-tolylacryloyl chloride and 5-methyl- N-(thiophen-2-ylmethyl)-lH-pyrazol-4-amine.
  • the said material was then completely dissolved in hot mixture of EtOH (5.0 mL) and DCM (2.0 mL). Upon cooling thick white needles started to form and the process was allowed to happen overnight. After decanting, the liquids were taken away with a pipette and the obtained solid was washed with three aliquots of cold EtOH. The obtained crystals were then heated in hot ethanol and the volatiles were then evaporated at the rotavap. This step was repeated 3 times in order to get rid of traces of DCM. The solids were then left overnight under high vacuum.
  • Example 174b N-(thiophen-2-ylmethyl)-lH-pyrazol-4-amine.
  • Example 185 Prepared in a similar manner to example 6 from 3-p-tolylpropanoyl chloride and N-
  • Example 204 Prepared in a similar manner to example 21 from cinnamoyl chloride and N-(thiophen-2- ylmethyl)ethanamine.
  • Example 233 Prepared in a similar manner to example 6 from 2-(cyclohexyloxy)acetyl chloride and N- (bicyclo[2.2.1]heptan-2-yl)-lH-pyrazol-5-amine.
  • Example 19 N-ethyl-2-(2-hydroxy-4-methylphenoxy)-N-(thiophen-2-ylmethyl)acetamide; Example 19. Prepared in a similar manner to example 5 from 2-(2-hydroxy-4-methylphenoxy)acetic acid and N-(thiophen-2-ylmethyl)ethanamine Yield 59 %.
  • Example 53 Prepared in a similar manner to example 5 from 2-(3-fluoropfienoxy)acetic acid and N- (thiophen-2-ylmethyl)aniline.

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Abstract

La présente invention concerne des composés utiles en tant que modulateurs de TRPM8, tels que des composés de Formule (I), et leur sous-genre et leurs espèces ; des produits personnelles contenant ces composés ; et l'utilisation de ces composés et des produits personnelles, en particulier l'utilisation d'augmentation ou d'induction de sensations chimioesthétiques, telles que des sensations de refroidissement ou de froid.
PCT/US2011/059312 2010-11-05 2011-11-04 Composés utiles en tant que modulateurs de trpm8 Ceased WO2012061698A2 (fr)

Priority Applications (15)

Application Number Priority Date Filing Date Title
PH1/2013/500907A PH12013500907A1 (en) 2010-11-05 2011-11-04 Compounds useful as modulators of trpm8
EP18199830.3A EP3470407B1 (fr) 2010-11-05 2011-11-04 Composés utiles comme modulateurs de trpm8
CN2011800534925A CN103201279A (zh) 2010-11-05 2011-11-04 作为trpm8的调节剂有用的化合物
RU2013125846A RU2608109C2 (ru) 2010-11-05 2011-11-04 Соединения, пригодные в качестве модуляторов trpm8
EP11838869.3A EP2635572B1 (fr) 2010-11-05 2011-11-04 Composés utiles en tant que modulateurs de trpm8
CA2816983A CA2816983A1 (fr) 2010-11-05 2011-11-04 Composes utiles en tant que modulateurs de trpm8
US13/883,349 US9394287B2 (en) 2010-11-05 2011-11-04 Compounds useful as modulators of TRPM8
JP2013537863A JP5990526B2 (ja) 2010-11-05 2011-11-04 Ｔｒｐｍ８の活性調節因子として有用な化合物
MX2013005001A MX340488B (es) 2010-11-05 2011-11-04 Compuestos utiles como moduladores de trpm8.
MX2016009042A MX359640B (es) 2010-11-05 2011-11-04 Compuestos utiles como moduladores de trpm8.
AU2011323245A AU2011323245B2 (en) 2010-11-05 2011-11-04 Compounds useful as modulators of TRPM8
BR112013011188-7A BR112013011188B1 (pt) 2010-11-05 2011-11-04 Método não-médico para modular canal potencial de receptor transiente de melastina 8 (trpm8), método não-médico para modular a sensação de resfriamento de uma composição, método não-médico para induzir uma sensação de resfriamento em um humano ou animal e composto
ZA2013/03421A ZA201303421B (en) 2010-11-05 2013-05-10 Compounds useful as modulators of trpm8
US15/205,608 US10016418B2 (en) 2010-11-05 2016-07-08 Compounds useful as modulators of TRPM8
US15/994,235 US10953007B2 (en) 2010-11-05 2018-05-31 Compounds useful as modulators of TRPM8

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